1. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells.
- Author
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Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ, Valenzuela DM, Yancopoulos GD, Karow M, Blander G, Wolberger C, Prolla TA, Weindruch R, Alt FW, and Guarente L
- Subjects
- Adenosine Diphosphate Ribose metabolism, Amino Acids pharmacology, Animals, Caloric Restriction, Cell Line, Tumor, Down-Regulation, Glucose pharmacology, Glutamate Dehydrogenase genetics, Glutamine pharmacology, Humans, Insulin metabolism, Insulin-Secreting Cells drug effects, Islets of Langerhans drug effects, Mice, Mice, Knockout, Mitochondria enzymology, NAD metabolism, Protein Processing, Post-Translational, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Sirtuin 1, Sirtuins genetics, Transfection, Glutamate Dehydrogenase metabolism, Insulin-Secreting Cells enzymology, Islets of Langerhans enzymology, Sirtuins metabolism
- Abstract
Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic beta cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR.
- Published
- 2006
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